We have performed studies using cultured human retinal pigment epithelial (RPE) cells as a model system to explore the regulation of gene expression in the RPE and have established that stearoyl-CoA destaurase, the rate limiting enzyme in the synthesis of unsaturated fatty acids, is expressed in RPE cells and is regulated by retinoic acid and TGF-b. In the course of these studies to evaluate the effect of all-trans retinoic acid and its derivatives on the regulation of gene expression in the ARPE-19 line of cultured RPE cells, we discovered that fenretinide (N(hydroxyphenyl)retinamide, 4-HPR), a synthetic retinoid, can induce neuronal-like differentiation in these cells. This effect was specific for fenretinide, since the differentiation was not seen in cells treated with other retinoids such as all-trans retinoic acid and 13-cis retinoic acid. The onset of ARPE-19 cell morphological changes to a neuronal phenotype induced by fenretinide was dose- and time-dependent, and the cells maintained the neuronal phenotype after withdrawal of fenretinide. The expression of neurofilament proteins 160 kDa and 200 kDa as well as N-CAM was increased in the differentiated cells. CRALBP, a protein normally expressed in RPE cells was decreased after 5 days of fenretinide treatment. The identification of factors capable of guiding the re-differentiation RPE cells to a neuronal phenotype will provide valuable tools for studying the process of retinal development and a potential pharmacological tool for the treatment of retinal degenerations. We have also performed studies to evaluate the effect of acute, intense visible light on the production of retinoic acid and retinoic acid-like compounds in the eyes of normal and transgenic rats carrying the P23H mutation in the opsin gene that has been demonstrated to render photoreceptor cells more susceptible to light damage. We have identified a compound in light exposed P23H retina and RPE/eyecup that has an absorbance maximum of 357 nm and a mass of 304, which is similar to retinoic acid. We did not observe this compound in the light exposed normal rat retina or RPE/ eyecup. Production of this retinoic acid-like compound was influenced by the age of the animals and the duration of light exposure. These results support the idea that a retinoid metabolite(s) may be an important factor in the retinal damage in P23H rats generated by exposure to intense visible light.